Treatment of pain or inflammation with p-benzoyl-phenylacetic acid or o-benzoyl-phenylacetic acid

ABSTRACT

PHARMACEUTICAL COMPOSITIONS COMPRISING AS ACTIVE INGREDIENT EITHER P-BENZOYL-PHENYLACETIC ACID, OR O-BENZOYLPHENYLACETIC ACID, WHICH COMPOUNDS MAY BE USED IN THE FORM OF PHYSIOLOGICALLY ACCEPTABLE SALTS. THESE ACTIVE INGREDIENTS HAVE ANTI-INFLAMMATORY AND ANALGETIC ACTIVITY. THEY MAY BE ADMINISTERED IN DOSAGE UNIT FORM.

United States Patent TREATMENT OF PAIhl 0R INFLAMMATION WITH P-BENZOYL-PHENYLACETIC ACID 0R O-BEN- ZOYL-PHENYLACETIC ACID Patented May 4, 1971 The daily dose of the active ingredient may be from about 25 to 750 mg. per day depending on the age, weight, and condition of the patient.

The present invention accordingly provides pharmaceutical compositions valuable in the treatment of inflamma- David Jack and Deryck Rhodes, London, England, as- 5 signors to Allen & Hanburys Limited, London, England tory conditions and also in conditions where the use of an No Drawing. Filed Aug. 9, 1968, Ser. No. 751,379 analgesic or antipyretic agent is indicated. Claims P y, application Great Britain, Allg- 1967, The compositions may be formulated for use in human 38,424/67 and veterinary medicine for therapeutic purposes. Such U 8 Cl A61k 27/00 2 Claims 10 compositions may be presented in a conventional manner with the aid of carriers and excipients and formulating agents as required and with or without supplementary ABSTRACT OF THE DISCLOSURE medlcmal agents- Preferably the composition Is in unit dosage form pllarmaeeuueal eomposltlons eonlpnslng as aetlve which expression as used herein means a physically disgredient either p-benzoyl-phenylacetic acid, or o-benzoy crete unit containing a predetermined dose of the active Phenylaeetle aeld, "Y compounds In51y be used in i compound in association with a pharmaceutical carrier or form of phys1olog1cally acceptable salts. These active" diluent The unit dosage f may contain 5 250 mg f ingredients have anti-inflammatory and analgetic activity. the active ingredient They may be administered in dosage unit form- The carrier or diluent may be solid or a liquid. In the former instance the composition of the present invention may exist in the form of, for example, capsules, supposi This invention relates to Pharmaceutical P tories or tablets which may include binders and lubricants More Particularly it relalfis i0 pharmaifeutical Composi' and which may be coated. If the carrier or diluent is a tiolls p fi e anti-inflammatory, antlpyretic anal liquid, the composition may be in unit dosage form, such geslc actlyltyas sterile solutions in ampoules for parenteral administra- The Compositions Provided y this invention Contain tion or solutions or suspensions in soft gelatine capsules as active ingredient either P' y -p y acid of for oral administration, or the compositions may be for Formula I o'benloyl-phenylacetic acid of Formula II example, suspensions or solutions for 'oral administration. or physiologically acceptable salts thereof The presentation of the active ingredients in the form of an aerosol spray, preferably metered, is sometimes P110 Q-M advantageous and such forms may be prepared by conventional methods. COPh The following examples illustrate the invention; 1 II EXAMPLE 1 In the formulae Ph=c6 H5 10,000 tablets containing 100 mg. of p-benzoylphenyl- The Preferred orgame and e Salts formed by acetic acid were prepared by the following technique: the free acids and organic and morgamc bases are those which have pharmacologically acceptable cations. Exam- G. ples of salts are those wherein the acidic hydrogen in the p-Benzoyl-phenylacetic acid 1,000 acids of Formulae I and II are replaced by one equivalent Calcium sulphate dihydrate 750 of a cation of an alkali metal such as sodium or potas- Dry maize starch 240 sium. Non-metallic cations include the ammonium ion, Magnesium stearate l0 substituted organic ammonium ions derived from primary secondary and tertiary amines and quaternary ammonium of Powdered P'benzoyl"phen ylacetlc acld was ions mixed with 750 g. of calcium sulphate dihydrate and sufii- These compounds have been found to possess anti cient of a 5% solution of low viscoslty sodium carboxyinflammatory and analgetic activity methylcellulose to produce a damp cohesive mass. This The screening tests used to detect anti-inflammatory 5 was granulated Y Passmg threllgh a 16 mesh Sleve- The activity were similar to those described by C. A. Winter, granules e dried 45-50 C- and passed through E. Risky, and Nuss, Expen Biol. & a 20 mesh sieve. The sieved granules were mixed with 240 Med. (1962), III, 541-544 and by C. G. Van Arman, gof maize starch and 10 g. of magneslum stearate. The A. Begany, L Miller and H. P1635, J. pharmacoL lubricated granules were compressed on a suitable tablet (1965), 150, 328-334 for the carrageenin test and H. machine using %2" e er normal concave p s to Konzett and R. Rossler. Arch. exp. Pathol. Pharmakol. Produce tablets of average Weight about 200 (1940), 195, 71-74 for the bradykinin test. Analgesic EXAMPLE 2 activity was assessed by the phenyl quinone-writhing and tail pinch tests in mice. Tablets Results of the tests are tabulated below: 100,000 sugar coated tablets containing mg. of p- Carrageenin Antibrady- Phenylquinone oral ED, kinin intraoral ED, milli- Tail clip oral ED, milligrams] venous Compound grams/kilograms milligrams/kilograms kilograms route p-Benzoyl phenyl, acetic acid 42.0 (27.9-63. 1) Weak activity, 50 19.0 (8. 7-41. 6) 0.6 (0.14.4) Indomethacin 2.5 (0.5425) .17.8 (8. 9-35. 6)

Aspirin benzoyl-phenyl acetic acid were prepared by the following technique:

Kg. p-Benzoyl-phenyl acetic acid 10 Calcium sulphate dihydrate 7.5 Dry maize starch i 2.4

Magnesium stearate 100 10 kg. of powdered p-benzoyl-phenyl acetic acid was mixed with 7.5 kg. of calcium sulphate dihydrate and sufficient of a solution of low viscosity sodium carboxymethylcellulose to produce a damp cohesive mass. This was granulated by passing through a 16 mesh sieve. The granules were dried at 4550 C. and passed through a 20 mesh sieve. The sieved granules were mixed with 2.4 kg. of maize starch and 100 g. of magnesium stearate. The lubricated granules were compressed on a suitable tablet machine using diameter deep concave punches to produce tablets of average weight about 200 mg. for coating.

The tablet cores were placed in a coating pan of suitable size. 200 ml. of a solution containing by weight of a polyvinylpyrrolidone and 2% by weight of polyethylene glycol 6000 in 66 o.p. industrial alcohol was applied. The solvents were caused to evaporate by means of cold air and the operation was repeated. The cores were heated to 45 C. by means of hot air and 200 ml. of a syrup containing 12% by weight of acacia gum and 66% by weight of sucrose applied. The tablets were allowed to roll until they were evenly coated with the syrup and were then dried by means of heated air. The last step was then repeated. The sugar coating was continued using a syrup containing 60% by weight of sucrose and 15% by weight of calcium phosphate until the average tablet weight was about 325 mg. Coating was continued using a syrup containing 66% by weight of sucrose and a suitable colouring agent until the average tablet weight was 350 mg. Finally the tablets were polished using conventionla techniques.

EXAMPLE 3 Tablets 100,000 enteric coated tablets each containing 100 mg. of p-benzoyl-phenyl acetic acid were prepared in the following way:

The tablet cores were prepared as in Example 2 above. The cores were rotated in a suitable coating pan and 200 ml. of a solution containing 10% by weight of a polyvinylpyrrolidone and 2% by weight of polyethylene glycol 6000 in 66 o.p. industrial alcohol was applied. The solvents were caused to evaporate by means of cold air and the operation was repeated. A film of cellulose acetate phthalate suitably plasticised was applied in a similar manner suflicient to enable the tablets to conform to the distintegration test for enteric coated tablets of the British Pharmacopoeia 1963, p. 1158.

The cellulose acetate phthalate was applied in solution in suitable mixed solvents such as acetone/ alcohol mixtures containing non toxic plasticisers such as castor oil, benzyl benzoate or glyceryl triacetate. When a satisfactory thickness of cellulose acetate phthalate had been applied the tablets were film coated using conventional methods.

EXAMPLE 4 Capsules Capsules each containing 50 mg. sodium p-benzoylphenylacetate were prepared using No. 4 hard gelatin capsules and sufficient microcrystalline cellulose to give a satisfactory fill.

EXAMPLE 5 Syrup A syrup suitable for oral administration was obtained, by dissolving 25 mg. of the sodium salt of p-benzoylphenylacetic acid in 10 mls. of the syrup vehicle. The syrup vehicle contained 50% w./v. sucrose and 10% glycerol. Suitable sweetening, flavoring and colouring agents were added and preserved with 0.1% of methyl p hydroxybenzoate together with 0.02% of propyl p-hydroxy benzoate.

o-Benzoyl-phenylacetic acid may be substituted for pbenzoyl-phenylacetic acid in the above examples.

We claim:

1. A method of treating a patient requiring analgetic or antiinflammatory treatment which comprises administering to said patient an analgesically and antiinflammatory effective non-toxic dose of a pharmaceutical composition comprising as active ingredient a member selected from the group consisting of p-benzoylphenylacetic acid, 0- benzoylphenylacetic acid, and physiologically acceptable salts thereof together with a pharmaceutically acceptable carrier.

2. A method in accord with claim 1 in which the composition is administered orally to the patient.

References Cited C. A. (1), 47-541f (1953). C. A. (2), -2343d (1961). C. A. (3), 58-5616b (1963). C. A. (4), 64-661a (1966).

STANLEY I. FRIEDMAN, Primary Examiner 

